1. Harvard University Initiative for Global Health Global Health Challenges Social Analysis 76: Lecture 8

2. Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Mycobacterium tuberculosis Infection Clinical Tuberculosis Preventive Interventions Treatment Interventions Global Distribution and Trends of Tuberculosis The Global Pattern The Decline of TB in High-Income Countries TB Epidemic in Sub-Saharan Africa Eastern Europe and Newly Independent States Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

3. Harvard University Initiative for Global Health TB is still a leading killer of young adults worldwide. Some 2 billion people – one-third of the world's population – are infected with the TB bacterium, M. tuberculosis. TB is a chronic bacterial infection. It is spread through the air and usually infects the lungs, although other organs are sometimes involved. Most persons that are infected with Mycobacterium tuberculosis harbor the bacterium without symptoms but many develop active TB disease. Tuberculosis

4. Harvard University Initiative for Global Health Transmission and Pathogenesis

5. Harvard University Initiative for Global Health 5% develop active clinical disease over the first 2 years after infection. 5-10% will develop active clinical disease sometime after 2 years. Reactivation of latent infection can occur many decades after infection. In a population, TB has a very long ‘memory’. Current disease incidence reflects transmission over many decades. Consequences of TB Infection

6. Harvard University Initiative for Global Health Rates of breakdown or reactivation from latent infection to clinical disease are dramatically higher for groups with reduced immune function. The most important risk factor for breakdown is HIV infection. Breakdown

7. Harvard University Initiative for Global Health When tuberculosis infection progresses to active disease it usually affects the lungs (85%) but can affect a range of other organ systems – called extrapulmonary disease. Two types of pulmonary clinical disease: sputum-smear positive (more infectious) and sputum culture positive. Without treatment, 50% die from pulmonary smear positive TB over 5 years of follow-up. Clinical Tuberculosis

8. Harvard University Initiative for Global Health

9. Diagnosing Latent Infection - Tuberculin skin test using purified protein derivative (PPD), read the test 24-48 hours after sub-dermal placement. Cross-reactivity with BCG - new interferon-  blood test, more specific Diagnosing clinical disease - sputum microscopy 100 year old technology - sputum culture, more sensitive - chest x-ray. Diagnostic Technologies

10. Harvard University Initiative for Global Health 1) 1)Decreasing probability of transmission: UV lights, negative air-pressure rooms, isolation 2) 2)BCG Vaccination – prevents childhood extrapulmonary tuberculosis, indeterminate efficacy for adult pulmonary tuberculosis. 3) 3)Chemoprophylaxis or preventive therapy for 2-6 months decreases breakdown by 60- 80%. 4) 4)Detection and treatment of smear positive cases reduces the risk of transmission. Preventive Interventions

11. Harvard University Initiative for Global Health WHO standard drug regimen uses 4 drugs for 2 months and then 2 drugs for 4 months. If completed, 90+% cure rate. Key issue is adherence to 6 months of therapy. WHO since 1994 recommends direct observation of patients taking medications. DOTS: Directly Observed Therapy, Short- Course. Drug regimens for MDR-TB are longer and more expensive. Standard Treatments

12. Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Mycobacterium tuberculosis Infection Clinical Tuberculosis Preventive Interventions Treatment Interventions Global Distribution and Trends of Tuberculosis The Global Pattern The Decline of TB in High-Income Countries TB Epidemic in Sub-Saharan Africa Eastern Europe and Newly Independent States Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

13. Harvard University Initiative for Global Health 1.6 Million Deaths 8.9 Million Cases

14. Harvard University Initiative for Global Health TB incidence declined for nearly 100 years in high-income countries. In mid-1980s, new cases increased in many countries for 5 or more years. TB also declined in most developing countries 1-3% per year. HIV infection has caused an epidemic of TB in high HIV prevalence countries. Trends in Tuberculosis

15. Harvard University Initiative for Global Health Reported TB Cases United States, 1953 - 1998 Year 10,000 20,000 * * 30,000 50,000 70,000 100,000 Cases (Log Scale) *Change in case definition 536070809098

16. Harvard University Initiative for Global Health

17. MDR-TB – multiple drug resistant tuberculosis has become a major issue in selected ‘hotspots’. Treatment success in cases with MDR-TB is much lower and costs much more. Limited evidence on the distribution of drug resistance. XDR – extensively drug resistant TB, ongoing major outbreak in Kwazulu Natal Multiple Drug Resistant TB

18. Harvard University Initiative for Global Health

19. Biology, Clinical Manifestations and Interventions Overview Mycobacterium tuberculosis Infection Clinical Tuberculosis Preventive Interventions Treatment Interventions Global Distribution and Trends of Tuberculosis The Global Pattern The Decline of TB in High-Income Countries TB Epidemic in Sub-Saharan Africa Eastern Europe and Newly Independent States Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

20. Harvard University Initiative for Global Health Before the advent of effective drugs, tuberculosis incidence was declining for 50 years in high-income countries. Decline could have been due to decreased transmission from better housing, the sanitoria movement or decreased breakdown from better nutritional status. History of Control (1)

21. Harvard University Initiative for Global Health Efforts to diagnose and treat TB in developing countries prior to 1980 were highly ineffective. In the 1980s, Karel Styblo demonstrated in Tanzania, Malawi and Mozambique that using more expensive but shorter regimens (6 months instead of 12-18 months) combined with hospitalization for the first 2 months and close supervision for the rest of the regimen, high cure rates in poor countries were possible. History of Control (2)

22. Harvard University Initiative for Global Health 1) 1)Individuals with symptoms of tuberculosis (chronic cough, hemoptysis, weight loss) will go to a clinic. 2) 2)Improving sputum microscopy at the primary care level will raise the case-detection rate. 3) 3)Raising the cure rate through directly observed therapy will lead to increased confidence from the public and higher case- detection. Principles Underlying DOTS

23. Harvard University Initiative for Global Health Rising case numbers in the West, the interaction of TB and HIV, and the widespread recognition that the Styblo model was cost-effective lead to increased attention for TB control in early 1990s. World Bank invested in exporting Styblo model to China in 1991. WHO reformulates the Styblo model as DOTS. History of Control (3)

24. Harvard University Initiative for Global Health WHO advocates for global targets of 70% case detection rate for smear-positives and 85% cure rate. In 1998, Global TB Programme reorganized into Stop TB Partnership. Shift in emphasis from national program reviews and technical support to global partnership activities. Major increase in % cured but slow increase in case detection rate. In 2003, GFATM starts disbursing for TB. History of Control (4)

25. Harvard University Initiative for Global Health WHO Global Tuberculosis Report 2006

26. Harvard University Initiative for Global Health WHO Global Tuberculosis Report 2006

27. Harvard University Initiative for Global Health Biology, Clinical Manifestations and Interventions Overview Mycobacterium tuberculosis Infection Clinical Tuberculosis Preventive Interventions Treatment Interventions Global Distribution and Trends of Tuberculosis The Global Pattern The Decline of TB in High-Income Countries TB Epidemic in Sub-Saharan Africa Eastern Europe and Newly Independent States Distribution of Drug Resistance History of the Health System Response Challenges and Controversies

28. Harvard University Initiative for Global Health New vaccines – many candidate vaccines now entering early clinical trial stage, 7-10 years new options may be available. New diagnostics including faster identification of multi-drug resistant tuberculosis becoming available. New Technologies

29. Harvard University Initiative for Global Health 1) 1)MDR-TB is being neglected. 2) 2)Tuberculosis incidence continues to rise in communities with high HIV sero-prevalence. 3) 3)Insisting on direct observation of therapy is not necessary and distracts from other efforts to increase case-detection. 4) 4)Preventive therapy is being ignored. 5) 5)Case-detection rates cannot be increased over 45% without addressing fundamental health system issues. Some Criticisms of DOTS Strategy

30. Harvard University Initiative for Global Health Does the global TB control strategy need to be changed to raise the case-detection rate? Should PT be used more? How much emphasis should be given to MDR- TB and XDR-TB in policy formulation? If new vaccines entering phase 1 clinical trials are protective, how will they change TB control? New Challenges